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Allosteric peptides that bind to a caspase zymogen and mediate caspase tetramerizationAllosteric peptides that bind to a caspase zymogen and mediate caspase tetramerization
Structural highlights
FunctionCASP6_HUMAN Involved in the activation cascade of caspases responsible for apoptosis execution. Cleaves poly(ADP-ribose) polymerase in vitro, as well as lamins. Overexpression promotes programmed cell death. Publication Abstract from PubMedThe caspases are a family of cytosolic proteases with essential roles in inflammation and apoptosis. Drug discovery efforts have focused on developing molecules directed against the active sites of caspases, but this approach has proved challenging and has not yielded any approved therapeutics. Here we describe a new strategy for generating inhibitors of caspase-6, a potential therapeutic target in neurodegenerative disorders, by screening against its zymogen form. Using phage display to discover molecules that bind the zymogen, we report the identification of a peptide that specifically impairs the function of caspase-6 in vitro and in neuronal cells. Remarkably, the peptide binds at a tetramerization interface that is uniquely present in zymogen caspase-6, rather than binding into the active site, and acts via a new allosteric mechanism that promotes caspase tetramerization. Our data illustrate that screening against the zymogen holds promise as an approach for targeting caspases in drug discovery. Allosteric peptides bind a caspase zymogen and mediate caspase tetramerization.,Stanger K, Steffek M, Zhou L, Pozniak CD, Quan C, Franke Y, Tom J, Tam C, Elliott JM, Lewcock JW, Zhang Y, Murray J, Hannoush RN Nat Chem Biol. 2012 Jun 10. doi: 10.1038/nchembio.967. PMID:22683611[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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